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EMBO J. 2017 Mar 15;36(6):761-782. doi: 10.15252/embj.201695000. Epub 2017 Jan 18.

Protein synthesis inhibition and GADD34 control IFN-β heterogeneous expression in response to dsRNA.

Author information

1
CNRS, INSERM, CIML, Aix Marseille University, Marseille, France.
2
International associated laboratory (LIA) CNRS "Mistra", Marseille, France.
3
Institute for Research in Biomedicine - iBiMED and Aveiro Health Sciences Program, University of Aveiro, Aveiro, Portugal.
4
CNRS, INSERM, CIML, Aix Marseille University, Marseille, France gatti@ciml.univ-mrs.fr pierre@ciml.univ-mrs.fr.

Abstract

In innate immune responses, induction of type-I interferons (IFNs) prevents virus spreading while viral replication is delayed by protein synthesis inhibition. We asked how cells perform these apparently contradictory activities. Using single fibroblast monitoring by flow cytometry and mathematical modeling, we demonstrate that type-I IFN production is linked to cell's ability to enter dsRNA-activated PKR-dependent translational arrest and then overcome this inhibition by decreasing eIF2α phosphorylation through phosphatase 1c cofactor GADD34 (Ppp1r15a) expression. GADD34 expression, shown here to be dependent on the IRF3 transcription factor, is responsible for a biochemical cycle permitting pulse of IFN synthesis to occur in cells undergoing protein synthesis inhibition. Translation arrest is further demonstrated to be key for anti-viral response by acting synergistically with MAVS activation to amplify TBK1 signaling and IFN-β mRNA transcription, while GADD34-dependent protein synthesis recovery contributes to the heterogeneous expression of IFN observed in dsRNA-activated cells.

KEYWORDS:

RIG‐I‐like receptors; cGAMP; integrated stress response; puromycin; stress granules

PMID:
28100675
PMCID:
PMC5350567
DOI:
10.15252/embj.201695000
[Indexed for MEDLINE]
Free PMC Article

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